The air raid targeted al-Jineh village, just over 30 km west of Aleppo, and razed to the ground the mosque during evening prayers - while the mosque was at its most full.
The US military confirmed that it had carried out a deadly airstrike in northern Syria and would investigate reports that civilians were killed when a mosque was struck in the raid.
The so-called Syrian Observatory for Human Rights said many people were still trapped under the collapsed mosque as rescue workers struggled to pull survivors from rubble, and dozens of residents were still unaccounted for.
Jineh is in the western Aleppo countryside, which along with Idlib is home to hundreds of thousands of Syrians displaced by fighting in other areas.
Abu Muhammed, a village resident, told AFP he heard powerful explosions when the mosque was hit. "It was right after the prayer at a time where there are usually religious lessons for men in it,” he said.
“I saw 15 bodies and lots of body parts in the debris when I arrived. We couldn’t even recognize some of the bodies,” he added.
The US-led coalition has been conducting airstrikes against what are said to be ISIS terrorists inside Syria since September 2014 without any authorization from the Damascus government or a UN mandate. It has also been involved in a similar campaign in neighboring Iraq.
The alliance has on many occasions attacked Syrian civilians, military and infrastructure under the guise of fighting the terror group.
There are also reports that the US-led attacks have on numerous occasions hampered counterterrorism operations by Syrian armed forces.
The latest US air raid came just after Syria contacted the United Nations to warn against an imminent disaster in the wake of air raids by the US-led military coalition close to the Euphrates and Tishrin dams.
Damascus urged UN Secretary General Antonio Guterres to help stop the attacks, “The total destruction of these dams that are being targeted by the airstrikes will wash away and flood cities, towns and villages, endangering the lives of hundreds of thousands of people living in those areas.”
Washington has currently between 800 and 900 Special Operations troops in Syria. A Pentagon official told AFP on Wednesday that the United States is set to deploy about 1,000 additional troops to the northern parts of the country.